The Harvard Aging Brain Study is sharing its data with the global research community. The longitudinal dataset consists of a 284-subject cohort with the following modalities acquired: demographics, clinical assessment, comprehensive neuropsychological testing, clinical biomarkers, and neuroimaging. To promote more extensive analyses, imaging data was designed to be compatible with other publicly available datasets. A cloud-based system enables access to interested researchers with blinded data available contingent upon completion of a data usage agreement and administrative approval. Data collection is ongoing and currently in its fifth year.

Furthering our understanding of the relationship between amyloidosis (Aβ), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimer's disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD.

The default-mode network (DMN) is a distributed functional-anatomic network implicated in supporting memory. Current resting-state functional connectivity studies in humans remain divided on the exact involvement of medial temporal lobe (MTL) in this network at rest. Notably, it is unclear to what extent the MTL regions involved in successful memory encoding are connected to the cortical nodes of the DMN during resting state. Our findings using functional connectivity MRI analyses of resting-state data indicate that the parahippocampal gyrus (PHG) is the primary hub of the DMN in the MTL during resting state. Also, connectivity of the PHG is distinct from connectivity of hippocampal regions identified by an associative memory-encoding task. We confirmed that several hippocampal encoding regions lack significant functional connectivity with cortical DMN nodes during resting state. Additionally, a mediation analysis showed that resting-state connectivity between the hippocampus and posterior cingulate cortex--a major hub of the DMN--is indirect and mediated by the PHG. Our findings support the hypothesis that the MTL memory system represents a functional subnetwork that relates to the cortical nodes of the DMN through parahippocampal functional connections.

Researchers employing Pittsburgh Compound B positron emission tomography (PIB-PET) imaging have consistently indentified old normal control (oNC) subjects with elevated tracer uptake, suggesting the presence of beta-amyloid deposition in these individuals. However, a consensus regarding the level at which PIB reveals a biologically meaningful signal does not exist (ie. an appropriate cutoff value for PIB positivity remains unclear). In this exploratory study, we sought to investigate the range of PIB distribution volume ratio (DVR) values present in our oNC cohort (N=75, age range=58-97). oNC subjects were classified based on global PIB index values (average DVR across prefrontal, parietal, lateral temporal and cingulate cortices) by employing two approaches: (1) an iterative outlier approach that revealed a cutoff value of 1.16 (IO-cutoff) and (2) an approach using data from a sample of young normal control subjects (N=11, age range=20-30) that yielded a cutoff value of 1.08 (yNC-cutoff). oNC subjects falling above the IO-cutoff had values similar to AD subjects ("PIB+", 15%). Subjects falling between the 2 cutoffs were considered to have ambiguous PIB status ("Ambig", 20%) and the remaining oNC were considered "PIB-" (65%). Additional measures capturing focal DVR magnitude and extent of elevated DVR values were consistent with the classification scheme using PIB index values, and revealed evidence for elevated DVR values in a subset of PIB- oNC subjects. Furthermore, there were a greater proportion of ambiguously elevated values compared to low values, and these elevated values were present in regions known to show amyloid deposition. The analyses presented in this study, in conjunction with recently published pathological data, suggest a biological relevance of slight PIB elevations in aging.

Anosognosia, or loss of insight of memory deficits, is a common and striking symptom in Alzheimer's disease (AD). Previous findings in AD dementia patients suggest that anosognosia is due to both functional metabolic changes within cortical midline structures involved in self-referential processes, as well as functional disconnection between these regions. The present study aims to extend these findings by investigating the neural correlates of anosognosia in the prodromal stage of AD. Here, we used regional brain metabolism (resting state 18-F fluorodeoxyglucose positron emission tomography (FDG-PET)) to unravel the metabolic correlates of anosognosia in subjects with amnestic mild cognitive impairment (aMCI) and subsequently resting state functional magnetic resonance imaging (rs-fMRI) to investigate the intrinsic connectivity disruption between brain regions. Thirty-one subjects (mean age: 74.1; Clinical Dementia Rating (CDR) global score: 0.5) with aMCI, and 251 cognitively normal (CN) older adults (mean age: 73.3; CDR: 0) were included as a reference group for behavioral and FDG data. An anosognosia index was obtained by calculating a discrepancy score between subjective and objective memory scores. All subjects underwent FDG-PET for glucose metabolism measurement, and aMCI subjects underwent additional rs-fMRI for intrinsic connectivity measurement. Voxel-wise correlations between anosognosia and neuroimaging data were conducted in the aMCI subjects. Subjects with aMCI had significantly decreased memory awareness as compared to the CN older adults. Greater anosognosia in aMCI subjects was associated with reduced glucose metabolism in the posterior cingulate (PCC) cortices and hippocampus. Intrinsic connectivity analyses revealed a significant association between anosognosia and attenuated functional connectivity between the PCC seed region and orbitofrontal cortex (OFC) as well as bilateral inferior parietal lobes (IPL). These findings provide further evidence that implicates cortical midline structures and hippocampus in the awareness of memory deficits. Investigating neuroimaging changes that co-vary with memory awareness may improve our ability to identify the cause of anosognosia and ultimately increase our chances for its treatment.

Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials.

Resting-state functional connectivity MRI (rs-fcMRI) is a non-invasive imaging technique that has come into increasing use to understand disrupted neural network function in neuropsychiatric disease. However, despite extensive study over the past 15 years, the development of rs-fcMRI as a biomarker has been impeded by a lack of reliable longitudinal rs-fcMRI measures. Here we focus on longitudinal change along the Alzheimer's disease (AD) trajectory and demonstrate the utility of Template Based Rotation (TBR) in detecting differential longitudinal rs-fcMRI change between higher and lower amyloid burden individuals with mildly impaired cognition. Specifically, we examine a small (N = 24), but densely sampled (~5 observations over ~3 years), cohort of symptomatic individuals with serial rs-fcMRI imaging and PiB-PET imaging for β-amyloid pathology. We observed longitudinal decline of the Default Mode and Salience network axis (DMN/SAL) among impaired individuals with high amyloid burden. No other networks showed differential change in high vs. low amyloid individuals over time. The standardized effect size of AD related DMN/SAL change is comparable to the standardized effect size of amyloid-related change on the mini-mental state exam (MMSE) and hippocampal volume (HV). Last, we show that the AD-related change in DMN/SAL connectivity is almost completely independent of change on MMSE or HV, suggesting that rs-fcMRI is sensitive to an aspect of AD progression that is not captured by these other measures. Together these analyses demonstrate that longitudinal rs-fcMRI using TBR can capture disease-relevant network disruption in a clinical population.

We determine whether diminished Learning Over Repeated Exposures (LORE) identifies subtle memory decrements in cognitively unimpaired (CU) older adults with Alzheimer's disease (AD) biomarker burden.

Proteinopathies are key elements in the pathogenesis of age-related neurodegenerative diseases, particularly Alzheimer's disease (AD), with the nature and location of the proteinopathy characterizing much of the disease phenotype. Susceptibility of brain regions to pathology may partly be determined by intrinsic network structure and connectivity. It remains unknown, however, how these networks inform the disease cascade in the context of AD biomarkers, such as beta-amyloid (Aβ), in clinically-normal older adults.The default-mode network (DMN), a prominent intrinsic network, is heavily implicated in AD due to its spatial overlap with AD atrophy patterns and tau deposition. We investigated the influence of baseline Aβ positron emission tomography (PET) signal and intrinsic DMN connectivity on DMN-specific cortical thinning in 120 clinically-normal older adults from the Harvard Aging Brain Study (73 ± 6 years, 58% Female, CDR = 0). Participants underwent11C Pittsburgh Compound-B (PiB) PET, 18F flortaucipir (FTP) PET, and resting-state MRI scans at baselineand longitudinal MRI (3.6 ± 0.96 scans; 5.04 ± 0.8 years). Linear mixed models tested relationships between baseline PiB and DMN connectivity on cortical thinning in a composite of DMN regions. Lower DMN connectivity was associated with faster cortical thinning, but only in those with elevated baseline PiB-PET signal. This relationship was network specific, in that the frontoparietal control network did not account for the observed association. Additionally, the relationship was independent of inferior temporal lobe FTP-PET signal. Our findings provide evidence that compromised DMN connectivity, in the context of preclinical AD, foreshadows neurodegeneration in DMN regions.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.

The ability to accurately judge memory efficiency (meta-memory monitoring) for newly learned (episodic) information, is decreased in older adults and even worse in Alzheimer's disease (AD), whereas no differences have been found for semantic meta-memory. The pathological substrates of this phenomenon are poorly understood. Here, we examine the association between meta-memory monitoring for episodic and semantic information to the two major proteinopathies in AD: amyloid (Aβ) and tau pathology in a group of cognitively unimpaired older adults. All participants underwent multi-tracer PET and meta-memory monitoring was assessed using a feeling-of-knowing (FOK) task for non-famous (episodic) and famous (semantic) face-name pairs. Whole brain voxel-wise correlations between meta-memory and PET data were conducted (controlling for memory), as well as confirmatory region-of-interest analyses. Participants had reduced episodic FOK compared to semantic FOK. Decreased episodic FOK was related to tauopathy in the medial temporal lobe regions, including the entorhinal cortex and temporal pole, whereas decreased semantic FOK was related to increased tau in regions associated with the semantic knowledge network. No association was found with Aβ-pathology. Alterations in the ability to accurately judge memory efficiency (in the absence of memory decline) may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase.

Individuals with Alzheimer's disease (AD) dementia exhibit significant heterogeneity across clinical symptoms, atrophy patterns, and spatial distribution of Tau deposition. Most previous studies of AD heterogeneity have focused on atypical clinical subtypes, defined subtypes with a single modality, or restricted their analyses to a priori brain regions and cognitive tests. Here, we considered a data-driven hierarchical Bayesian model to identify latent factors from atrophy patterns and cognitive deficits simultaneously, thus exploiting the rich dimensionality within each modality. Unlike most previous studies, our model allows each factor to be expressed to varying degrees within an individual, in order to reflect potential multiple co-existing pathologies. By applying our model to ADNI-GO/2 AD dementia participants, we found three atrophy-cognitive factors. The first factor was associated with medial temporal lobe atrophy, episodic memory deficits and disorientation to time/place ("MTL-Memory"). The second factor was associated with lateral temporal atrophy and language deficits ("Lateral Temporal-Language"). The third factor was associated with atrophy in posterior bilateral cortex, and visuospatial executive function deficits ("Posterior Cortical-Executive"). While the MTL-Memory and Posterior Cortical-Executive factors were discussed in previous literature, the Lateral Temporal-Language factor is novel and emerged only by considering atrophy and cognition jointly. Several analyses were performed to ensure generalizability, replicability and stability of the estimated factors. First, the factors generalized to new participants within a 10-fold cross-validation of ADNI-GO/2 AD dementia participants. Second, the factors were replicated in an independent ADNI-1 AD dementia cohort. Third, factor loadings of ADNI-GO/2 AD dementia participants were longitudinally stable, suggesting that these factors capture heterogeneity across patients, rather than longitudinal disease progression. Fourth, the model outperformed canonical correlation analysis at capturing associations between atrophy patterns and cognitive deficits. To explore the influence of the factors early in the disease process, factor loadings were estimated in ADNI-GO/2 mild cognitively impaired (MCI) participants. Although the associations between the atrophy patterns and cognitive profiles were weak in MCI compared to AD, we found that factor loadings were associated with inter-individual regional variation in Tau uptake. Taken together, these results suggest that distinct atrophy-cognitive patterns exist in typical Alzheimer's disease, and are associated with distinct patterns of Tau depositions before clinical dementia emerges.

In the present study, we tested the hypothesis that higher amyloid-beta (Aβ) burden at baseline is associated with greater longitudinal decline in body mass index (BMI) in clinically normal adults. Participants from the Harvard Aging Brain Study (n = 312) and the Alzheimer's Disease Neuroimaging Initiative (n = 336) underwent Aβ positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years. Linear mixed models showed that higher baseline Aβ burden was significantly associated with greater decline in BMI in both the Harvard Aging Brain Study (t = -1.93; p = 0.05) and Alzheimer's Disease Neuroimaging Initiative cohorts (t = -2.54; p = 0.01), after adjusting for covariates, including cognitive performance and depressive symptoms. In addition, the association of Aβ burden with longitudinal decline in BMI persisted in both cohorts after excluding participants with diabetes/endocrine disturbances and participants classified as underweight or obese (BMI <18.5 or >30). These findings suggest that decline in BMI in clinically normal adults may be an early manifestation related to cerebral amyloidosis that precedes objective cognitive impairment. Therefore, unintentional BMI decline in otherwise healthy individuals might alert clinicians to increased risk of Alzheimer's disease.

To reduce the rising incidence of clinical impairment due to Alzheimer disease, it is essential to define older adults at highest risk. Widowhood may be an unrecognized factor contributing to accelerated clinical progression along the Alzheimer disease pathway among cognitively unimpaired older adults.

Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer's disease (AD) continuum. A key methodological step in tau PET analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal flortaucipir ([18F]-AV1451) PET scans were examined using several common reference regions (e.g., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A+) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A+) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A+, and MCI A+ groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging when using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.

Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer's disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials.

Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

The integrated Alzheimer's Disease Rating Scale (iADRS) is a validated cognitive/functional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures.

Alzheimer's disease (AD) heritability is enriched in glial genes, but how and when cell-type-specific genetic risk contributes to AD remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets. In an autopsy dataset spanning all stages of AD (n=1,457), astrocytic (Ast) ADPRS was associated with both diffuse and neuritic Aβ plaques, while microglial (Mic) ADPRS was associated with neuritic Aβ plaques, microglial activation, tau, and cognitive decline. Causal modeling analyses further clarified these relationships. In an independent neuroimaging dataset of cognitively unimpaired elderly (n=2,921), Ast-ADPRS were associated with Aβ, and Mic-ADPRS was associated with Aβ and tau, showing a consistent pattern with the autopsy dataset. Oligodendrocytic and excitatory neuronal ADPRSs were associated with tau, but only in the autopsy dataset including symptomatic AD cases. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.

We investigated the effect of baseline Aβ, sex, and APOE on longitudinal tau accumulation in cerebrospinal fluid (CSF) in clinically normal older adults. Two hundred thirty-nine participants (aged 56-89 years, clinical dementia rating = 0) underwent serial CSF collection for Aβ1-42, total-tau (t-tau) and phospho-tau181P (p-tau). We used preprocessed data from fully automated Roche Elecsys immunoassays. A series of linear regressions were used to examine cross-sectional effects of Aβ1-42, sex, and APOEε4 on baseline CSF tau and linear mixed models for longitudinal changes in CSF tau. Cross-sectionally, CSF t-tau and p-tau were associated with abnormal Aβ1-42 and APOEε4 but not with sex. Longitudinally, low baseline CSF Aβ1-42 levels, but not APOEε4 or sex, predicted faster p-tau accumulation. The relationship between baseline CSF Aβ1-42 and tau accumulation was strongest in APOEε4 carriers, and particularly female carriers, relative to other groups. The current findings support an association between baseline CSF Aβ1-42 and changes in CSF tau. Elevated risk in females, apparent only in carriers, reinforces findings of sex-related vulnerability in those with genetic predisposition for Alzheimer's disease.